RESUMO
We have observed that systemic administration of cannabinoid CB1 antagonists exerts antiparkinsonian effects in rats with very severe nigral lesion (>95% cell loss), but not in rats with less severe lesion (85-95% cell loss). Local injections into denervated striatum and corresponding globus pallidus reduced parkinsonian asymmetry. Infusions into lesioned substantia nigra enhanced motor asymmetries, but this effect was absent after very severe nigral lesion. At the striatal level, CB1 antagonists act enhancing dopamine D1 receptor function and reducing D2 receptor function. Striatal dopaminergic denervation did not affect cannabinoid CB1 receptor coupling to G proteins. These results suggest that (i) systemic administration of CB1 antagonists in rats with severe nigral degeneration is ineffective because striatopallidal-mediated motor effects are antagonized by nigra-mediated activity, and (ii) CB1 antagonists exert antiparkinsonian effects after very severe nigral degeneration because nigra-mediated inhibition disappears. CB1 receptor antagonists that lack psychoactive effects might be of therapeutic value in the control of very advanced stage of Parkinson's disease in humans.
Assuntos
Antiparkinsonianos/uso terapêutico , Canabinoides/antagonistas & inibidores , Transtornos Parkinsonianos/tratamento farmacológico , Receptor CB1 de Canabinoide/antagonistas & inibidores , Substância Negra/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Transtornos Parkinsonianos/fisiopatologia , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/fisiologia , Rimonabanto , Substância Negra/fisiologiaRESUMO
Brain cannabinoid CB(1) receptors are expressed in neural areas that contribute to movement such as basal ganglia, where they co-localize with dopamine D(1) and D(2) receptors. The objective of the present study was to further study the functional role of CB(1) receptors along with D(1) and D(2) dopamine receptors of basal ganglia by local injections of SR141716A (CB(1) receptor antagonist), SKF-38393 (D(1) agonist), and quinpirole (D(2) agonist), in a rat Parkinson's model. Turning response after amphetamine was considered as the parkinsonian variable for quantifying motor effects of drugs. The findings indicated that, after intrastriatal infusions, both D(1) or D(2) dopamine receptor agonists alone reduced turning in parkinsonian rats. At the pallidal and subthalamic levels, D(1) (not D(2)) receptor stimulation also reduced rotation. Regarding SR141716A-induced effects, CB(1) antagonism reduced motor asymmetry in parkinsonian rats after injections into striatum, globus pallidus, and to a lesser extent, subthalamic nucleus. At the level of dorsal striatum, effects of SR141716A were mediated through an opposite modulation of D(1) and D(2) dopamine receptor function. At the pallidal and subthalamic nucleus levels, motor effects after SR14716A are not associated to modulation of D(1) and D(2) receptor function.
Assuntos
Globo Pálido/efeitos dos fármacos , Neostriado/efeitos dos fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Animais , Modelos Animais de Doenças , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Rimonabanto , Núcleo Subtalâmico/efeitos dos fármacosRESUMO
Modulation of the endocannabinoid system might be useful in treating Parkinson's disease. Here, we show that systemic administration of N-(4-hydroxyphenyl)-arachidonamide (AM404), a cannabinoid modulator that enhances anandamide (AEA) availability in the biophase, exerts antiparkinsonian effects in 6-hydroxydopamine-lesioned rats. Local injections of AM404 into denervated striata reduced parkinsonian motor asymmetries, these effects being associated with the reduction of D2 dopamine receptor function together with a positive modulation of 5-HT(1B) serotonin receptor function. Stimulation of striatal 5-HT(1B) receptors alone was observed to ameliorate parkinsonian deficits, supporting the fact that AM404 exerts antiparkinsonian effects likely through stimulation of striatal 5-HT(1B) serotonin receptor function. Hence, modulation of cannabinoid function leading to enhancement of AEA in the biophase might be of therapeutic value in the control of symptoms of Parkinson's disease. On the other hand, reduced levels of N-acyl-transferase (AEA precursor synthesizing enzyme), without changes in fatty acid amidohydrolase (AEA degradative enzyme), were detected in denervated striata in comparison with intact striata. This finding reveals the presence of a homeostatic striatal mechanism emerging after dopaminergic denervation likely tending to enhance low dopamine tone.